JP2013533866A - Process for preparing a single enantiomer of 3-aminopiperidine dihydrochloride - Google Patents

Abstract

(A) reduction of N-acetyl-3-aminopyridine (2) or a salt thereof in the presence of hydrogen and a palladium catalyst deposited on a solid support, (b) the racemic formed in step (a). Conversion of isomer N-acetyl-3-aminopiperidine (3) or a salt thereof to rac-3-aminopiperidine (rac-4) or a salt thereof, (c) racemic 3-amino produced in step (b) A method comprising resolution of piperidine (rac-4) or a salt thereof with a chiral acid. In one aspect, the solid support for palladium is carbon, calcium carbonate, titania, or zirconia.

Description

(Introduction)
The present application relates to a process for the preparation of any enantiomer of 3-aminopiperidine dihydrochloride having a high% enantiomeric excess and to compound (R) -piperidine-3 having an enantiomeric excess of greater than 98% -Relates to a process for the preparation of either amines or (S) -piperidin-3-amines. The present application specifically relates to a process for preparing (R) -3-aminopiperidine dihydrochloride having an enantiomeric excess of greater than 98%.

  The salt, 3-aminopiperidine dihydrochloride, is a component for several drugs. Patent Document 1 published on July 5, 2007 and incorporated by reference in its entirety includes the hydrogenation of rhodium-catalyzed 3-aminopyridine, resolution with dibenzoyltartaric acid, and MTBE (methyl tert- The acid exchange using hydrogen chloride in (butyl ether) is described. This did not result in an improvement in enantiomeric purity and therefore the dibenzoyl tartrate salt of 3-aminopiperidine had to be repeatedly recrystallized before acid exchange. There is a need to identify solvent systems that improve the yield by reducing the number of recrystallization steps in the process by increasing the enantiomeric purity at this stage.

  U.S. Patent No. 6,057,051 describes the hydrogenation of 3-aminopyridine at 50 ° C and 100 bar hydrogen pressure using a 5 wt% platinum / rhodium mixed catalyst in acetic acid. Heterocycles, 1993, 36 (10), 2383 provides three products by reducing 3-aminopyridine using samarium iodide in THF (of which 3-aminopiperidine is 26% It is produced in a yield). Berichte der Deutschen Chemischen Geschelschft [Abtelung] B: Abhandlugen, 1937, 70B, 635, describes the hydrogenation of 3-aminopyridine in methanol and hydrochloric acid catalyzed by platinum oxide. U.S. Patent No. 6,057,051 describes the hydrogenation of several α, γ-dicarbonyl substituted 3-aminopyridine derivatives using platinum oxide in either acetic acid or methanol and hydrochloric acid. J. et al. Med. Chem. , 1980, 23, 848, 3-N-acetyl-aminopyridine using platinum oxide in methanol and concentrated hydrochloric acid, yield 47% after basification and isolation of 3-N-acetamido-piperidine. Explains the hydrogenation of. This reaction took 42 hours. Adv. Synth. Catal. , 2008, 350, 807 describe the kinetic resolution of 1-Boc-3-aminopiperidine by the transaminase enzyme with a 97% enantiomeric excess and a yield of 42%. This reaction was performed at a concentration of 10 mM with respect to 1-Boc-3-aminopiperidine and provided the (R) enantiomer. U.S. Patent No. 6,057,033 discloses (R) -3-aminopiperidine dihydrochloride from D-ornithine via esterification, ring closure to aminoamide, and reduction using lithium aluminum hydride at 60 ° C followed by treatment with hydrochloric acid. The synthesis method is described. This method was accompanied by a complex precipitation of the hydrochloride. Synthetic Communications, 1998, 28, 3919 describes the synthesis of (R) -3-aminopiperidine dihydrochloride from D-glutamic acid. This includes esterification, amine protection, ester reduction using sodium borohydride / calcium chloride, activation using mesyl chloride and subsequent substitution with benzylamine followed by benzyl groups using palladium / carbon and hydrogen. Includes removal of.

International Publication No. 2007/075630 US Patent Application Publication No. 2006/0142310 International Publication No. 95/08536 International Publication No. 2007/112368

  Any single of 3-aminopiperidine dihydrochloride that improves enantiomeric purity, eliminates the need for repeated recrystallization of 3-aminopiperidine dibenzoyl tartrate, and uses a less expensive palladium catalyst There remains a need to provide improved methods for the preparation of enantiomers.

  In one aspect, the present application provides a process for the preparation of any enantiomer of 3-aminopiperidine dihydrochloride ((R) -4 or (S) -4), hydrogen chloride in isopropyl alcohol / water as solvent. Provides a process involving an improvement in chiral purity, including direct acid exchange from a partially resolved 3-aminopiperidine chiral acid salt.

  In another aspect, the present application specifically relates to a process for the preparation of (R) -3-aminopiperidine dihydrochloride having an enantiomeric excess of greater than 98%, comprising hydrogen chloride in isopropyl alcohol / water as solvent. Relates to a process involving an improvement in chiral purity, including direct acid exchange from a partially resolved 3-aminopiperidine chiral acid salt according to.

(Detailed explanation)
In one aspect, the present application provides a process for the preparation of any enantiomer of 3-aminopiperidine dihydrochloride ((R) -4 or (S) -4), hydrogen chloride in isopropyl alcohol / water as solvent. Provides a process involving an improvement in chiral purity, including direct acid exchange from a partially resolved 3-aminopiperidine chiral acid salt.

  In another aspect, the present application provides a process for the preparation of (R) -3-aminopiperidine dihydrochloride ((R) -4), partially resolved with hydrogen chloride in isopropyl alcohol / water as solvent. Provided is a process involving an improvement in chiral purity involving direct acid exchange from aminopiperidinedibenzoyl- (D) -tartrate (5).

一態様において、本願はさらに、単離をしないｒａｃ−３−アミノピペリジンジヒドロクロリド（ｒａｃ−４）の中和と、前記３−アミノピペリジンジベンゾイル−（Ｄ）−酒石酸塩（５）の形成とを含む。この反応は、高いジアステレオマー純度（ｄｉａｓｔｅｒｅｏｉｓｏｍｅｒｉｃ ｐｕｒｉｔｙ）でのジアステレオマー塩を提供する。

In one embodiment, the application further comprises neutralizing rac-3-aminopiperidine dihydrochloride (rac-4) without isolation and formation of said 3-aminopiperidinedibenzoyl- (D) -tartrate (5). including. This reaction provides diastereomeric salts with high diastereoisomeric purity.

一態様において、所望により、本願はさらに、３−アミノピペリジンジベンゾイル−（Ｄ）−酒石酸塩（５）のジアステレオマー純度の向上を含んでいてもよい。

In one embodiment, if desired, the application may further include an improvement in the diastereomeric purity of 3-aminopiperidinedibenzoyl- (D) -tartrate (5).

一態様において、本願はさらに、単離することなく形成されるＮ−アセチル−３−アミノピリジン（２）の水素化を含み、ｒａｃ−Ｎ−アセチル−３−アミノピペリジン酢酸塩（３）が提供される。該水素化は、固体支持体上のパラジウム触媒を使用して実施されてもよい。該固体支持体は、炭素、炭酸カルシウム、チタニア、またはジルコニアであってもよい。一実施形態において、該水素化は、パラジウム炭素の存在下で実施されてもよい。

In one aspect, the application further comprises hydrogenation of N-acetyl-3-aminopyridine (2) formed without isolation, providing rac-N-acetyl-3-aminopiperidine acetate (3). Is done. The hydrogenation may be carried out using a palladium catalyst on a solid support. The solid support may be carbon, calcium carbonate, titania, or zirconia. In one embodiment, the hydrogenation may be performed in the presence of palladium on carbon.

一態様において、本願はさらに、３−アミノピリジン（１）からのその場での（ｉｎ ｓｉｔｕ）Ｎ−アセチル−３−アミノピリジン（２）の形成を含む。

In one aspect, the present application further includes the formation of in situ N-acetyl-3-aminopyridine (2) from 3-aminopyridine (1).

一態様において、本願はさらに、ｒａｃ−Ｎ−アセチル−３−アミノピペリジン酢酸塩（３）におけるアセチル基の酸性加水分解および後続のエタノールとの共沸性乾燥によるｒａｃ−３−アミノピペリジンジヒドロクロリドｒａｃ−（４）の形成を含む。

In one aspect, the present application further provides rac-3-aminopiperidine dihydrochloride rac by acidic hydrolysis of the acetyl group in rac-N-acetyl-3-aminopiperidine acetate (3) followed by azeotropic drying with ethanol. -Including formation of (4).

前記酸交換反応は通常、約２〜約１０モル当量の塩酸、典型的には約２〜約４モル当量の範囲の塩酸により行われる。一実施形態において、塩酸のモル当量は少なくとも約２であり、別の実施形態においては少なくとも約３である。しかしながら、該反応は、約５程度の高いモル当量の塩酸を使用しても実施され得る。

The acid exchange reaction is usually carried out with about 2 to about 10 molar equivalents of hydrochloric acid, typically in the range of about 2 to about 4 molar equivalents. In one embodiment, the molar equivalent of hydrochloric acid is at least about 2, and in another embodiment is at least about 3. However, the reaction can also be carried out using molar equivalents of hydrochloric acid as high as about 5.

  Improvement of the diastereomeric purity of 3-aminopiperidinedibenzoyl- (D) -tartrate (5) is optionally about 5 v / w to about 50 v / w, typically about 10 v / w to (5) It may be carried out using an alcohol solvent in an amount of about 25 v / w. In one embodiment, the amount of alcohol solvent for (5) is at least 20 v / w, and in another embodiment is at least about 25 v / w. However, this reaction can also be carried out using as much alcohol solvent as about 30 for (5). In one embodiment, the alcohol solvent is methanol. The reaction time to improve the diastereomeric purity of 3-aminopiperidinedibenzoyl- (D) -tartrate (5) is typically from about 0.5 hours to about 48 hours. In one embodiment, the time to improve the diastereomeric purity is about 1 hour to about 24 hours, and is at least about 2 hours.

  Suitable bases for the neutralization step include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide and the like. The neutralization reaction typically employs from about 1.0 to about 4.0 molar equivalents of a suitable base with respect to rac-4. In one embodiment, a suitable base molar equivalent for rac-4 is from about 2.0 to about 3.0, and in another embodiment, a suitable base molar equivalent for rac-4 is at least about 2. .05. The neutralization reaction typically uses methanol in an amount of about 5 to about 30 v / w with respect to rac-4. In one embodiment, an amount of methanol of about 10 to about 20 v / w is used for rac-4, and in another embodiment, an amount of methanol of about 14.5 v / w is used for rac-4. Suitable acids for the resolution reaction include either (D) -DBTA or a chiral non-racemic acid described in WO 2007/078630. The resolution reaction typically employs a suitable chiral non-racemic acid, such as about 0.5 to about 4.0 molar equivalents of (D) -DBTA with respect to rac-4. In one embodiment, a suitable chiral non-racemic acid, such as about 0.5 to about 2.0 molar equivalents of (D) -DBTA with respect to rac-4, is added at least 1.07 molar equivalents of ( D) A suitable chiral non-racemic acid such as -DBTA is used. The resolution reaction is usually heated above room temperature, typically in the range of about 44 ° C to about 84 ° C. In one embodiment, the reaction temperature is from about 54 ° C to about 74 ° C. In one embodiment, the reaction temperature is increased to at least about 60 ° C, and in another embodiment, to at least about 64 ° C. However, the reaction can also be carried out at temperatures as high as about 80 ° C. The time for the resolution reaction is typically from about 0.5 hours to about 48 hours. In one embodiment, the time is about 1 hour to about 24 hours, at least about 2 hours.

  The hydrogenation reaction is usually carried out above atmospheric pressure, typically in the range of about 2 bar to about 500 bar. In one embodiment, the pressure is from about 5 bar to about 100 bar. In one embodiment, the pressure rises to at least about 20 bar, and in another embodiment, the pressure rises to at least about 10 bar. However, the reaction can also be carried out at pressures as high as about 90 bar. In the hydrogenation reaction, the amount of Pd / C added for (2) is typically in the range of about 0.5 wt% to about 200 wt%. In one embodiment, the Pd / C addition is from about 1% to about 100% by weight. In one embodiment, the Pd / C loading for (2) is at least about 5% by weight and in another embodiment is at least about 3.5% by weight. However, the reaction can also be carried out with a Pd / C addition as high as about 50% by weight with respect to (2). The hydrogenation reaction is usually heated above room temperature, typically in the range of about 20 ° C to about 140 ° C. In one embodiment, the temperature is from about 25 ° C to about 120 ° C. In one embodiment, the temperature rises to at least about 60 ° C and in another embodiment to at least about 80 ° C. However, the reaction can also be carried out at temperatures as high as about 100 ° C. The duration of the hydrogenation reaction is typically about 3 hours to 7 days. In one embodiment, the time is from about 1 hour to about 24 hours, and in another embodiment is at least about 3 hours. Suitable solvents for the hydrogenation reaction include acetic acid, propionic acid, butanoic acid, or any carboxylic acid that is liquid under the reaction conditions.

  Suitable reagents for the in situ acylation reaction include acetic anhydride, acetyl chloride, or any carboxylic acid chloride, propionic anhydride, butanoic anhydride, or any carboxylic anhydride. Suitable solvents for the in situ acylation reaction include acetic acid, propionic acid, butanoic acid, or any carboxylic acid that is liquid under the reaction conditions. The in situ acylation reaction is typically cooled below room temperature, typically in the range of about 0 ° C to about 25 ° C. In one embodiment, the temperature is from about 10 ° C to about 25 ° C. However, the reaction can also be carried out at temperatures as high as about 120 ° C. The in situ acylation reaction is usually carried out using about 1.0 to about 20 molar equivalents of an acylating agent, typically in the range of about 1 to about 10 molar equivalents. In one embodiment, about 1 to about 5 molar equivalents of acylating agent is used. In one embodiment, the molar equivalent of the acylating agent is at least about 1.0, and in another embodiment is at least about 1.05. However, the reaction can also be carried out with as high a molar equivalent acylating agent as about 2.5. The in situ acylation reaction is usually carried out at (1) in acetic acid at a concentration of about 2 v / w to about 10 v / w. In one embodiment, the concentration of (1) in acetic acid is about 4 v / w. The time of the in situ acylation reaction is typically about 1 hour to 2 days. In one embodiment, from about 2 hours to about 24 hours, and in another embodiment, about 2 hours.

  Suitable acids for the acidic hydrolysis reaction include hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, tetrafluoroboric acid, hydrofluoric acid, hydroiodic acid, perchloric acid, or any suitable inorganic acid. Is included. Suitable solvents for the acidic hydrolysis reaction include ethanol, methanol, 2-propanol, or any suitable alcohol solvent. The acidic hydrolysis reaction is typically carried out with an acid strength in the range of about 0.5M to about 12M. In one embodiment, the acid strength is from about 1M to about 12M. In one embodiment, the acid strength is at least about 3M, and in another embodiment is at least about 6M. However, the reaction can also be carried out with acid strengths as high as about 10M. The acidic hydrolysis reaction is usually carried out with about 1 to about 30 molar equivalents of acid, typically in the range of about 1 to about 20 molar equivalents. In one embodiment, the molar equivalent of acid is at least about 2, and in another embodiment is at least about 3. However, the reaction can also be carried out using molar equivalents of acid as high as about 5. The volume of alcohol for (3) used each time in the acidic hydrolysis reaction is typically about 1 v / w to about 20 v / w. In one embodiment, the alcohol volume for (3) is about 1.2 v / w. The number of alcohol dissolution / concentration cycles used in the acidic hydrolysis reaction is typically from about 1 to about 10. In one embodiment, the number of alcohol dissolution / concentration cycles used is about 3.

スキーム１は、本願の実施例の合成の概略を示す。

Scheme 1 outlines the synthesis of the examples of the present application.

  The method involves fewer recrystallization steps, uses less expensive catalysts such as Pd / C, the use of lower pressure, produces a single product with higher yields, and is a faster reaction . The method provides either enantiomer of the product by switching the resolving agent, whereas the transaminase pathway requires finding an (S) -selective enzyme. Unlike the transaminase route, this route is carried out at a practical and industrially preferred concentration and allows good raw material throughput.

(Definition)
The following definitions are used in connection with the present application unless otherwise indicated. Celite ™ is a flux calcined diatomaceous earth. Celite ™ is a registered trademark of World Minerals Inc. Is a registered trademark. DBTA is dibenzoyl-tartaric acid, HPLC is high pressure liquid chromatography, MeOH is methanol, and CROWNPAK ™ is a HPLC column containing a chiral crown ether coated on 5 μm silica as a chiral selective agent. Point to. Crownpak ™ is a product of DAICEL CHEMICAL. It is a registered trademark of INDUSTRIES, LTD. The term “enantiomeric excess (%)” means the enantiomeric excess of a substance and is defined as the absolute difference between the molar fractions of each enantiomer. The term “de” means “diastereomeric excess”, ie, one diastereomeric pair of enantiomers (assuming two asymmetric centers) exceeds the other pair of enantiomers, NMR is nuclear magnetic resonance. As used herein, the term “reacting” is intended to refer to combining chemical reactants under conditions that induce the indicated chemical reaction.

An “alcohol solvent” is an organic solvent containing carbon bonded to a hydroxyl group. "Alcohol solvents" include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol) 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2- or 3-pentanol, neopentyl alcohol, t-pentyl Alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerin, C _1-6 alcohol, etc. are included. It is not limited to it.

  A “chiral acid” is usually used for resolution of nitrogen-containing compounds. “Chiral acid” includes (1R or 1S) -10-camphorsulfonic acid, (D or L) -tartaric acid, (D or L) -dibenzoyltartaric acid, (1R or 1S) -3-bromocamphor-10-sulfone Acid, (R or S) -1,1 "-binaphthyl-2,2" -diyl-hydrogen phosphate, (D or L) -di-O, O'-p-toluoyl-tartaric acid, (D or L) -Di-O, O'-o-toluoyl-tartaric acid, (D or L) -N-acetyl-phenylalanine, (D or L) -acetyl mandelic acid, (R or S) -cyclohexyl phenyl glycolic acid, (S) Camphoric acid, (R or S) -2-pyrrolidone-5-carboxylic acid, naproxen, ibuprofen, (D or L) -tartaric acid, (D or L) -malic acid, L-lactic acid, (R or S) -3- hydroxybutyric acid, or including but hyodeoxycholic acid, and the like.

  Comparing the hydrogenation for 3-aminopyridine in acetic acid and 3-N-acetylaminopyridine in acetic acid explains the higher reactivity of N-acetyl derivatives.

本願の方法の実施に使用される手順を実施例において説明する。説明される手順に関する妥当な変法は、本発明の範囲内に含まれるものとする。

The procedure used to carry out the method of the present application is described in the examples. Reasonable variations on the described procedure are intended to be included within the scope of the present invention.

Example 1: Preparation of rac-3-aminopiperidine dihydrochloride (rac-4) Acetic anhydride (91.63 g, 897.5 mmol) was added to 3-aminopyridine (1, 80.48 g, 855.) in acetic acid (400 mL). 2 mmol) of the solution cooled to 10 ° C. over 10 minutes. An exotherm of 15 ° C. was observed. Once the addition was complete, the solution was stirred at room temperature for 2 hours and then added to a glass liner with 5% palladium / carbon (12.24 g). After storage in a pressure vessel, the solution was filled with nitrogen to a pressure of 10 bar, stirred until equilibrium was reached and degassed. This nitrogen filling / stirring / degassing cycle was repeated twice. The vessel was then degassed by filling it with hydrogen to a pressure of 10 bar without stirring. This hydrogen filling / degassing cycle was repeated twice. The vessel was then filled to a hydrogen pressure of 10 bar, heated to 80 ° C. and stirred, while maintaining the pressure between 9.9 and 101 bar. After 3 hours, the hydrogen consumption ceased. The contents were cooled to room temperature, the vessel was filled with nitrogen to a pressure of 10 bar, stirred for 20 minutes and then degassed. After repeating this nitrogen filling / stirring / degassing cycle one more time, the contents were filtered through Celite ™ and washed with acetic acid (40 mL). The filtrate was partially concentrated in vacuo to 280.04 g bulk weight (61 wt% acetic acid solution assuming 100% conversion / yield). Hydrochloric acid (428 mL of 6M solution, 2568 mmol) was added to the acetic acid solution and heated to reflux for 18 hours. The solution was cooled to room temperature and concentrated in vacuo. Ethanol (200 mL) was charged to the residue and then concentrated in vacuo. This ethanol loading / concentration method was repeated two more times using the same amount of solvent to give the title compound as a white solid (120.6 g, 81%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δppm 9.50-8.50 (4H, br), 3.48-3.42 (2H, m), 3.39-3.30 (1H, br), 3.19 (1H, br d, J 12 Hz ), 2.90 (1H, t, J 12 Hz), 2.77 (1H, td, J 12 and 3 Hz), 2.05 (1H, br d, J10 Hz), 1.88 (1H, dt, J 12 and 3 Hz) ), 1.78-1.69 (1H, m), and 1.61 (1H, qd, J12, and 3 Hz).

Example 2: Preparation of (R) -3-aminopiperidinedibenzoyl- (D) -tartrate (5) Sodium hydroxide (10.3 g in 46-48% solution, 4.74 g ai, 118. 5 mmol) was added dropwise to an ice-water bath cooled suspension of rac-3-aminopiperidine dihydrochloride (rac-4, 10.0 g, 57.8 mmol) in methanol (145 mL). Once the addition was complete, the solution was stirred at room temperature for 1 hour and then filtered (pass through a filter paper with a porosity of 3: 4.90 g of sodium chloride was recovered, 71% of theory). 2 mL). Dibenzoyl- (D) -tartaric acid (22.16 g, 61.84 mmol) was then added to the solution followed by heating to 60 ° C. (very gentle reflux) for 2 hours. The resulting suspension was cooled to 20 ° C. over 1-2 hours and then stirred at this temperature for 20 hours. This solid was collected by filtration, washed successively with a mixture of methanol (19 mL) and water (1 mL), then methanol (20 mL), and dried in vacuo to give the title compound in 13.2% diastereomeric excess white. Obtained as a solid (19.9 g, 75%).

Example 3: Improving the diastereomeric excess of (R) -3-aminopiperidinedibenzoyl- (D) -tartrate (5) (R) -3-aminopiperidinedibenzoyl- (D) in methanol (465 mL) A suspension of tartrate (5, 18.6 g, 40.6 mmol, 13.2% diastereomeric excess) was heated to 60 ° C. for 2 hours (very gentle reflux) and then 1 to 20 ° C. After cooling over 2 hours, the mixture was stirred at this temperature for 19 hours. The suspension was filtered and the residue was washed with fresh methanol (2 × 18 mL) and then dried in vacuo to give the title compound as a white solid (8.28 g, 44%) with a 96.5% diastereomeric excess. Got as.

Example 4: Preparation of (R) -3-aminopiperidine dihydrochloride (R-4) Hydrogen chloride (7.2 mL of 5-6 M 2-propanol solution, 36 mmol assuming 5 M) was added at 30 ° C. Add dropwise to a suspension of (R) -3-aminopiperidinedibenzoyl- (D) -tartrate in -propanol (5, 30 mL) and water (1.9 mL). After stirring at this temperature for 1 hour, the mixture was heated to 60 ° C. to obtain a clear solution. After stirring at this temperature for 90 minutes, the solution was cooled to 20 ° C. over 1-2 hours and then stirred at this temperature for 18 hours. This solid was collected by vacuum filtration using a stream of nitrogen, then successively with a mixture of 2-propanol (2.1 mL) and water (0.1 mL), then 2-propanol (3 × 2.2 mL). Washed. Filtration and washing operations were performed under vacuum and a stream of nitrogen. The solid was dried in vacuo (50 ° C., 12 mbar) to give the title compound as a white solid (1.64 g, 79%) with an enantiomeric excess of 99.6%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δppm 7.97 (4H, d, J 8 Hz), 7.64 (2H, t, J 8 Hz), 7.52 (4H, t, J 8 Hz), 5.61 (2H, s), 3.06 (2H, br d, J 9 Hz), 2.79 (1H, br d, J 12 Hz), 2.63 (1H, dd, J 12 and 10 Hz), 2.48-2.43 (1H, m), 1.76 -1.67 (1H, m), 1.54-1.42 (1H, m), and 1.37-1.23 (2H, m).

Example 5: Preparation of rac-3-aminopiperidine dihydrochloride (rac-4) Acetic anhydride (65.1 g, 638 mmol) was added to 10 ° C of 3-aminopyridine (50.0 g, 531 mmol) in acetic acid (150 mL). It was dripped at the cooled solution over 10 minutes. An exotherm of 15 ° C. was observed. Once the addition was complete, the solution was stirred at room temperature for 2 hours and then added to a glass liner with 10% palladium / carbon (2.5 g). After storage in a pressure vessel, the solution was filled with nitrogen to a pressure of 10 bar, stirred until equilibrium was reached and degassed. This nitrogen filling / stirring / degassing cycle was repeated twice. The vessel was then degassed by filling it with hydrogen to a pressure of 1-2 bar without stirring. This hydrogen filling / degassing cycle was repeated twice. The vessel was then filled to 10 bar and heated to 80 ° C. and stirred while maintaining the pressure between 16 and 20 bar. After 10 hours, the hydrogen consumption ceased. The contents were cooled to room temperature, the vessel was filled with nitrogen to a pressure of 10 bar, stirred for 20 minutes and then degassed. After this nitrogen filling / stirring / degassing cycle was repeated once more, the contents were filtered through Celite ™ and washed with acetic acid (12.5 mL). The filtrate was completely concentrated in vacuo to a bulk weight of 150 g. Hydrochloric acid (125 mL, 35% solution) was added to the acetic acid solution and heated to reflux for 12 hours. The solution was cooled to room temperature and concentrated in vacuo. Isopropyl alcohol (150 mL) was charged to the residue and then concentrated in vacuo. This isopropyl alcohol loading / concentration method was repeated two more times using the same amount of solvent to give the title compound as a white solid (80.5 g, 87%).

Example 6: Preparation of (R) -3-aminopiperidinedibenzoyl- (D) -tartrate (5) Sodium hydroxide (44.3 g of a 10-12% solution, 4.74 g ai, 118. 5 mmol) was added dropwise to an ice-water bath cooled suspension of rac-3-aminopiperidine dihydrochloride (10.0 g, 57.8 mmol) in methanol (70 mL). Once the addition was complete, the solution was stirred at room temperature for 1 hour, filtered through a filter paper with a porosity of 3 (4.90 g sodium chloride was recovered, 71% of theory) and the solid was washed with methanol (10 mL) Washed. Dibenzoyl- (D) -tartaric acid (22.16 g, 61.84 mmol) was then added to the solution followed by heating to 60 ° C. for 2 hours (very gentle reflux). The resulting suspension was cooled to 20-25 ° C. over 1-2 hours and then stirred at 20-25 ° C. for 8 hours. The reaction mixture was then further cooled to −10 to −5 ° C. and stirred at this temperature for 8 hours. The solid was collected by filtration, washed with methanol (10 mL) and dried in vacuo to give the title compound as a white solid (10.8 g, 41%) with a 93% diastereomeric excess.

Example 7: Preparation of (R) -3-aminopiperidine dihydrochloride (R-4) Hydrogen chloride (7.2 mL of 5-6 M isopropyl alcohol solution, 36 mmol assuming 5 M) was added isopropyl alcohol (30 mmol at 30 ° C). To a suspension of (R) -3-aminopiperidinedibenzoyl- (D) -tartrate (5.5 g, 12 mmol) in 30 mL) and water (1.65 ml). After stirring at this temperature for 1 hour, the mixture was heated to 60 ° C. After stirring at this temperature for 90 minutes, the solution was cooled to 20 ° C. over 1-2 hours and then stirred at this temperature for 18 hours. The solid was collected by filtration under vacuum using a stream of nitrogen and then washed sequentially with a mixture of isopropyl alcohol (5.5 mL). Filtration and washing operations were performed under vacuum and a stream of nitrogen. The solid was dried in vacuo (50 ° C., 12 mbar) to give the title compound as a white solid (1.7 g, 82%) with an enantiomeric excess of 99.0%.

Mirror images for (R) -3-aminopiperidine dihydrochloride (R-4) and for the determination of the estimated diastereomeric excess of (R) -3-aminopiperidinedibenzoyl- (D) -tartrate (5) Isomeric purity assay HPLC conditions Column: Crownpak ™ CR + (150 × 4.6 mm)
Mobile phase: 95: 5v / v HClO ₄ of (pH1): MeOH (70% of _{16.27g HClO 4 -> H 2 O} = pH1 of 1L)
Flow rate: 0.6 mL / min Column temperature: 0 ° C
Detection: Refractive index (Gilson 133 sensitivity 2)
Injection: 5 μL
Standard preparation: After adding about 5 mg to 300 μL of MeOH, 700 μL of HClO ₄ (pH 1) is added Retention time (S) 3.0 minutes (R) 3.7 minutes.

  The compounds described herein have asymmetric centers. Compounds of the present application that contain asymmetric substituents can be isolated in optically active or racemic forms. Methods for preparing optically active forms are well known in the art, for example, by resolution of racemic forms or synthesis from optically active starting materials. Structures drawn for compounds within this application are intended to include all isomeric (eg, enantiomeric) forms of the structures. For example, R and S compatible configurations at the stereogenic carbon are included in this application.

Structures drawn for compounds within this application are also intended to include all isomeric (eg, enantiomeric or conformational) forms of the structures. For example, R and S compatible configurations at the stereogenic carbon are included in this application. Therefore, single stereochemical isomers as well as enantiomeric and conformational mixtures of the present compounds are included within the scope of the present application. Methods for preparing optically active forms, for example by resolution of racemic forms or synthesis from optically active starting materials, are well known in the art. In addition, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having this structure are included within the scope of this application, except for replacement of hydrogen with deuterium or tritium, or replacement of carbon with ¹³ C enriched or ¹⁴ C enriched carbon.

  Various publications are cited throughout this application. The disclosures of these publications are hereby incorporated by reference herein in order to more fully describe the state of the art known to those skilled in the art as of the date of this application as described and claimed herein. Is incorporated by reference.

  While particular embodiments of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. Therefore, all such changes and modifications that are within the spirit of this invention are intended to be covered by the appended claims.

Claims (17)

(A) Reduction of N-acetyl-3-aminopyridine (2) or a salt thereof in the presence of hydrogen and a palladium catalyst deposited on a solid support:

(B) Conversion of racemic N-acetyl-3-aminopyridine (3) or a salt thereof produced in step (a) to rac-3-aminopiperidine (rac-4) or a salt thereof:

(C) Resolution of racemic 3-aminopiperidine (rac-4) or salt thereof produced in step (b) with a chiral acid:

Including a method.   The method of claim 1, wherein the solid support for palladium is carbon, calcium carbonate, titania, or zirconia.   The method of claim 3, wherein the solid support is carbon.   The method of claim 1, wherein the hydrogen pressure is above atmospheric pressure.   5. The method of claim 4, wherein the hydrogen pressure is from about 2 bar to about 500 bar.   6. The method of claim 5, wherein the hydrogen pressure is at least about 10 bar. The chiral acid in step (c) is dibenzoyl- (D) -tartaric acid and the salt formed is 3-aminopiperidinedibenzoyl- (D) -tartrate (5):

The method of claim 1, wherein Formation of N-acetyl-3-aminopyridine (2) or a salt thereof from 3-aminopyridine (1) by reaction with an acetylating agent:

The method of claim 1, further comprising:   9. The method of claim 8, wherein the acetylating agent is acetic anhydride, acetyl chloride, or a mixture thereof.   The method of claim 9, wherein the acetylating agent is acetic anhydride. If desired, further improvement of the diastereomeric purity of 3-aminopiperidinedibenzoyl- (D) -tartrate (5) by further heating in an alcohol solvent:

The method of claim 7 comprising:   The method of claim 11, wherein the alcohol solvent is methanol. Direct acid exchange from partially resolved 3-aminopiperidinedibenzoyl- (D) -tartrate (5) with hydrogen chloride in isopropyl alcohol / water as the solvent:

The method of claim 7, further comprising:   The method according to claim 8, wherein the acetylation of the 3-aminopyridine (1) is carried out in the presence of acetic acid, propionic acid or butyric acid.   The process according to claim 14, wherein the acetylation of the 3-aminopyridine (1) is carried out in the presence of acetic acid.   The method according to claim 8, wherein the salt of N-acetyl-3-aminopyridine (2) is acetate, propionate, or butyrate.   The process according to claim 16, wherein the salt of N-acetyl-3-aminopyridine (2) is acetate.